RESUMEN
BACKGROUND: Type 2 diabetes is a major health problem affecting millions of people. Controlled eating and regular physical activity are important for the management of type 2 diabetes. Dipeptidyl peptidase-4 enzyme (DPP-4) inhibitor sitagliptin is a potent agent for the treatment of type-2 diabetes. The aim of this study was to examine the effects of sitagliptin on the liver of rats with streptozotocin (STZ)-induced diabetes, in terms of (i) the expression levels of the cannabinoid 1 receptor (CB-1R) and glucagon-like peptide 1 receptor (GLP-1R), (ii) alterations in the number and localization of these peptides, and (iii) changes in histological and oxidative damage. METHODS: Thirty-two neonatal (two-day-old) rats, which were divided into four groups, were treated with saline (control), sitagliptin (control; 1.5mg/kg/day for 15 days starting from day 5 of the experimental period), STZ (diabetes; 100mg/kg single dose), STZ+sitagliptin (diabetes+sitagliptin). After 20 days, hepatic tissues were obtained from rats. RESULTS: The expressions of GLP-1R and CB-1R mRNA increased approximately 1.89- and 2.94-fold, respectively, in the diabetes+sitagliptin group as compared to the diabetic group. Additionally the number of GLP-1R immunopositive cells decreased and CB-1R immunopositive cells increased in comparison to the diabetic group; however, this was not statistically significant. Glutathione levels increased, but malondialdehyde and protein carbonyl levels decreased in the diabetes+sitagliptin group more than the diabetic group. CONCLUSION: Our findings indicate that sitagliptin treatment regulates GLP-1R and CB-1R gene expressions, which are associated with appetite regulation in diabetic rat, and may decrease oxidative stress and liver tissue damage.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Hipoglucemiantes/farmacología , Estrés Oxidativo/efectos de los fármacos , Receptor Cannabinoide CB1/metabolismo , Fosfato de Sitagliptina/farmacología , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón/genética , Hipoglucemiantes/uso terapéutico , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Receptor Cannabinoide CB1/genética , Fosfato de Sitagliptina/uso terapéuticoRESUMEN
BACKGROUND: Diabetes is a major public health problem that is rapidly increasing in prevalence. In this study, the effects of sitagliptin, a dipeptidyl peptidase-4 inhibitor, were examined on newborn diabetic rat model. METHODS: Wistar albino newborn rats were divided into control (Ctrl), sitagliptin (Sit), diabetic and diabetic+Sit groups. On the second day after the birth, 100mg/kg streptozotocin (STZ) was administered intraperitoneally in a single dose to induce type-2 diabetes in rats. The Sit and diabetic+Sit groups were administered sitagliptin (1.5mg/kg subcutaneous) as of the day 5 for 15 days. The pancreas sections were stained with insulin (INS), glucagon (GLU), somatostatin (SS), glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-1 receptor (GLP-1R) antibodies by the streptavidin-biotin peroxidase technique. The TUNEL method for apoptosis and biochemical analysis were performed in the pancreas and serum, respectively. RESULTS: Body weight and blood glucose levels showed significant differences among all groups on days 11 and 20. In diabetic rats following treatment with sitagliptin, the area percentage of INS immunopositive cells increased while the area percentage of SS immunopositive cells decreased, insignificantly. A significant increase was observed on the area percentage of GLU, GLP-1 and GLP-1R immunopositive cells in the diabetic+Sit group when compared to the diabetic group. The area percentage of apoptotic cells was the same among all groups. While serum glutathione and malondialdehyde levels demonstrated insignificant alterations, the catalase and superoxide dismutase activity significantly changed among four groups. CONCLUSION: According to our findings, sitagliptin may be a useful therapeutic agent to a certain extent of type-2 diabetic condition.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Fosfato de Sitagliptina/farmacología , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/patología , Glucagón/metabolismo , Péptido 1 Similar al Glucagón/metabolismo , Islotes Pancreáticos/patología , Ratas , Ratas Wistar , Somatostatina/metabolismoRESUMEN
Ghrelin is a multifunctional peptide hormone which stimulates appetite and regulates glucose metabolism and adipogenesis. The purpose of this study was to investigate whether ghrelin has protective effects in the liver of streptozocin (STZ) diabetic rats or not. Wistar-type neonatal rats were divided into four groups: I. Controls, II. Ghrelin administrated controls, III. STZ-diabetic rats, and IV. Ghrelin administrated diabetic rats. On the second day after birth, 100 mg/kg STZ was administered intraperitoneally in a single dose to induce diabetes in rats. 100 µg/kg/day ghrelin was administrated to rats subcutaneously for 4 weeks. Ghrelin administration improved histopathologic changes in STZ-diabetic liver. Obestatin immunoreactivity has been shown in livers of neonatal rats. The immunoreactivity of obestatin increased in diabetic rats and a decline was observed in ghrelin administrated diabetic rats. Caspase 8 and 3 immunoreactivities increased in diabetic rats; however, ghrelin administration differently affected caspases 8 and 3 immunoreactivities. Proliferating cell nuclear antigen immunoreactivities decreased in diabetic rats and in ghrelin administrated diabetic rats. Serum alanine (P < 0.05) and aspartate transaminase (P < 0.0001) and serum alkaline phosphatase (P < 0.0001) activities were decreased in ghrelin administrated diabetic rats compared to the diabetic rats. Gamma glutamyl transferase activity (P < 0.001) decreased in ghrelin administrated diabetic rats compared to the diabetic rats. The response of antioxidants including glutathione levels, catalase and superoxide dismutase activities were altered in ghrelin administrated diabetic rats. Our findings indicate that ghrelin administration affects hepatic functions in neonatal diabetic rats and might be considered as a therapeutic agent.